Pili are hair-like adhesive organelles found on a wide variety of pathogenic bacteria that are employed to adhere to and colonize host tissues by binding to receptors in the host tissues. Pili are heteropolymeric surface fibers with an adhesive tip and consist of two major sub-assemblies, the pilus rod and the tip fibrillum. The pilus rod is a thick rigid rod made up of repeating subunits arranged in a right handed helical cylinder whereas the tip fibrillum is a thin, flexible tip fiber extending from the distal end of the pilus rod and is composed primarily of repeating subunits arranged in an open helical configuration. Periplasmic chaperones are involved in a molecular mechanism necessary for guiding biogenesis of adhesive organelles in Gram-negative bacteria. These periplasmic chaperones facilitate the assembly of competent complexes from subunits. The periplasmic chaperones are so critical to the functioning of the pili that in the absence of an interaction with the chaperone, pilus subunits aggregate and are proteolytically degraded. Pathogenic Gram-negative bacteria include organisms such as Escherichia coli, Haemophilus influenzae, Salmonella enteriditis, Salmonella typhimirium, Bordetella pertussis, Yersinia pestis, Yersinia enterocolitca, Helicobacter pylori and Klebsiella pneumoniae. 
The prevention or inhibition of normal pilus assembly in Gram-negative bacterium impacts the pathogenicity of the bacterium by preventing the bacterium from infecting host tissues. Drugs that interfere with the assembly of pili should effectively disable pathogens responsible for a wide variety of Gram-negative infections, such as those responsible for bladder, kidney and middle ear infections as well as food poisoning, gastric ulcers, diarrhea, meningitis, and other illnesses. Drugs that interfere with the assembly of pili are known collectively as pilicides.
One class of pilicides that has been developed are those with a β-lactam-like structure. These pilicides are described in patent application Ser. No. 9/252,792, entitled β-Lactam-Like Chaperone Inhibitors, invented by Scott Hultgren/Fredrik Almqvist.
Certain compounds noted for other structural components but containing 2-pyridinone substructures have been reported to possess medicinal properties. Some of these compounds are suggested to be antibacterial and antifungal agents and some are disclosed as free radical scavengers. Free radicals play a role in a variety of diseases, including cardiovascular disease, connective tissue damage, inflammatory disorder and CNS injury. See Zhang et al, Cyclobutenedione-Based Method for the Synthesis of Substituted 2-Pyridinones and Dihydro-2-pyridinones, J.Org.Chem. 1999, 64, 4042-4049; Casinovi, et al, A New Antibiotic Produced By A Strain of Aspergillus Flavipes, Tetrahedron Letters, No. 27, 3175-3178.
N-substituted 2-pyridinones themselves have been employed as active ingredients for the therapy of fibrotic disease and have been evaluated as inhibitors of human leukocyte elastase. Margolin, S. B. U.S. Pat. No. 5,310,562. Some synthetic 2-pyridinones have also demonstrated high hypotensive or cardiotropic activity. Grontas, W. C., Stanga, M. A., Brobaker, M. J., Huang T. L., Moi, M. L., Carroll, R. T. J. Med. Chem. 1985, 28, 1106. The usefulness of these pyridinones has generated intense interest in the medical applications of pyridinones and consequently the synthesis of compounds containing a 2-pyridinone substructure has become increasingly important. However, N-substituted, 2-pyridinones have not previously been known to interfere with pilus formation in Gram-negative bacteria.
A number of methods for the preparation of substituted 2-pyridinones have been reported in the literature and are known. One such method involves the oxidation of pyridinium salts to the corresponding 2-pyridinones with ferricyanide under basic conditions. Although the synthesis is straightforward, the method is limited by the availability of the corresponding pyridinium salts. Many 2-pyridinone methodologies incorporate the Michael addition, the nucleophilic addition of carbanions to α,β-unsaturated ketones, as a key step in the formation of six-membered rings. Cycloaddition procedures have also been employed to synthesize 2-pyridinones.
In Cyclobutenedione-Based Method for the Synthesis of Substituted 2-Pyridinones and Dihydro-2-pyridinones, J. Org. Chem. 64,11:4042 authors Shijie Zhang and Lanny Liebeskind report a synthesis of a 1,2 addition of N-Boc protected α-amino carbanions to cyclobutenediones, subsequent methylation, and thermal ring expansion. Treatment with NBS/pyridine yielded the desired substituted 2-pyridinones.
Solid phase synthesis has been employed in the preparation of certain pyridinones. In Solid Phase Synthesis of 1,3,5-Trisubstituted Pyridin-2-ones, Tetrahedron Letters, 40(1999) 2227-2230 authors James A. Linn et al. report the solid phase synthesis of 1,3,5-trisubstituted pyridin-2-ones via selective NH-alkylation of 3-amino-5-carbomethoxy-1H-pyridin-2-one using a solid supported halo-acid. The synthesis proceeds by the coupling of 6-bromohexanoic acid to a Rink amine macrocrown to form a solid-supported 6-bromohexanamide. The solid-supported 6-bromohexanamide was used to alklylate 3-amino-5-carbomethoxy-1H-pyridin-2-one which was then reacted with diphenylacetic acid. Saponification of the resulting ester yielded a solid supported carboxylic acid. Treatment of the solid supported carboxylic acid with pentafluorophenol provided the pentafluorophenyl ester, which when treated with benzylamine was cleaved from the macrocrown to give the pyridinone. However, a solid phase synthesis procedure to produce ring fused 2-pyridinones has not yet been reported.
Many of the known methods of production of pyridinones create a racemic mixture of compounds rather than one enantiomer of the compound. Thus, although a number of synthetic routes to produce pyridinones are known, some of which are functional group tolerant, there is continuing interest in novel, straightforward, regioselective and functional group tolerant synthetic methods, due to the roles 2-pyridinones and compounds containing a 2-pyridinone substructure play in a variety of medical applications. Solid phase synthesis procedures specifically for the production of the pyridinone substructure are desirable because of the ability of this synthetic procedure to yield relatively pure compounds. Thus, solid phase synthesis possesses the additional advantage of the simplicity of purifying compounds produced by it in addition to the advantages of being regioselective and functional group tolerant. Solid phase synthesis is particularly useful in the making of libraries for biological testing and biological uses; solid phase synthesis is amenable to the use of automation by machines.
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